This proposal focuses on understanding the mechanism responsible for sleep disorder comorbidities associated with epilepsy. Sleep is essential for survival. Lack of appropriate durations and quality of sleep is detrimental to centra and peripheral physiological functions that, if left unchecked, can have long-term deleterious consequences ranging from cognitive, immunological, hormonal, metabolic and psychological disorders. In patients with epilepsy, the third most common neurological disorder, lack of sleep can increase seizures, thus exacerbating the core syndrome, and worsen other concomitant disorders such as cognitive impairments and psychological comorbidities. At least one third of epilepsy patients are afflicted with sleep disorder comorbidities, however, because sleep disorders are often overlooked, a realistic estimate may be much higher. Current therapies for epilepsy and its comorbidities are largely symptomatic due to a lack of understanding the underlying disease mechanisms. Therefore, detailed studies elucidating the causes of sleep disorder comorbidities are needed to discover new therapeutic strategies and improve the quality of life of patients with epilepsy. Many of the types of sleep disorders associated with epilepsy are similar to those experienced by people (without epilepsy) which involve a dysregulation of the hypocretin system. Hypocretin neurons are located in the lateral hypothalamus and stimulate arousal nuclei to elicit wakefulness and in sleep disorders, trigger inappropriate awakenings. This proposal is based on the overall premise that pathology exists in the lateral hypothalamus of epileptics that reduces adenosine-inhibition of hypocretin neurons, which ultimately contributes to sleep disorder comorbidities. Using a genetic model of epilepsy with broad clinical relevance, we propose to demonstrate that in LH of epileptic mice (1) there is a pathology that is associated reduced adenosine levels; (2) adenosine A1 receptor-mediated inhibition of hypocretin neurons is diminished; (3) hypocretin protein is elevated and activity of hypocretin neurons is enhanced during periods of rest; and (4) activation of adenosine A1 receptors is necessary for the somnogenic effects of the ketogenic diet. The proposed studies, spanning in vivo and in vitro systems using a combination of techniques in molecular biology, chemistry, electrophysiology and circadian physiology will provide insight into the mechanism of sleep disorder comorbidities associated with epilepsy. The results will have tremendous translational potential by identifying and validating new therapeutic targets for restoring effectie sleep to epilepsy patients. Furthermore, effectively treating sleep disorders has the potential to reduce seizures and improve other comorbidities also experienced by a significant portion of the epileptic population. These results will be relevant to other neurological diseases with sleep disorder comordities and astrocytic pathology as a common denominator. PUBLIC HEALTH RELEVANCE: At least one third of epilepsy patients are afflicted with sleep disorder comorbidities, however, because sleep disorders are often overlooked, a realistic estimate may be much higher. Lack of effective sleep can increase seizures, thus exacerbating the core syndrome, and worsen other concomitant disorders such as cognitive impairments and psychological comorbidities. Therefore, detailed studies elucidating the mechanisms of these sleep disorders are needed to discover new therapeutic strategies and improve the quality of life of patients with epilepsy.